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WO2024252327A1 - Formes solides de n-(méthoxycarbonyl)-3-méthyl-l-valyl-(4r)-n- {(1s)-1-cyano-2-[(3s)-2-oxopyrrolidin-3-yl]éthyl}-4-(trifluorométhyl)-l-prolinamide et leurs solvates - Google Patents

Formes solides de n-(méthoxycarbonyl)-3-méthyl-l-valyl-(4r)-n- {(1s)-1-cyano-2-[(3s)-2-oxopyrrolidin-3-yl]éthyl}-4-(trifluorométhyl)-l-prolinamide et leurs solvates Download PDF

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Publication number
WO2024252327A1
WO2024252327A1 PCT/IB2024/055548 IB2024055548W WO2024252327A1 WO 2024252327 A1 WO2024252327 A1 WO 2024252327A1 IB 2024055548 W IB2024055548 W IB 2024055548W WO 2024252327 A1 WO2024252327 A1 WO 2024252327A1
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ppm
peaks
peak
ethyl
methyl
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WO2024252327A8 (fr
Inventor
Kapildev Kashmirilal ARORA
Maria GONZALEZ ESGUEVILLAS
Samir Kulkarni
Aifang Li
Paul Anthony MEENAN
Nandini PATEL
Jeanene Elizabeth Tickner
Xiaojing Yang
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Pfizer Corp Belgium
Pfizer Corp SRL
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Pfizer Corp Belgium
Pfizer Corp SRL
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Publication of WO2024252327A8 publication Critical patent/WO2024252327A8/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to solid forms of /V-(Methoxycarbonyl)-3-methyl-L-valyl- (4R)-/V- ⁇ (1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L- prolinamide and solvates thereof, pharmaceutical compositions comprising the solid forms, and methods of preparing and using the solid forms and pharmaceutical compositions.
  • the compound of Formula I inhibits viral proteases such as coronavirus main proteases and thereby inhibits the viral replication process.
  • the compound of Formula I is for use in the treatment of coronavirus infections such as SARS-CoV-2 infections (COVID-19).
  • Solid forms are of interest to the pharmaceutical industry and especially to those involved in the development of suitable dosage forms. If the solid form is not held constant during clinical or stability studies, the exact dosage form used or studied may not be comparable from one lot to another. It is also desirable to have processes for producing a compound with the selected solid form in high purity when the compound is used in clinical studies or commercial products since impurities present may produce undesired toxicological effects. Certain solid forms may also exhibit enhanced stability or may be more readily manufactured in high purity in large quantities, and thus are more suitable for inclusion in pharmaceutical formulations. Certain solid forms may display other advantageous physical properties such as lack of hygroscopic tendencies, filterability, improved solubility, and enhanced rates of dissolution due to different lattice energies.
  • Solid forms of the compound of Formula I and solid forms of certain solvates thereof are disclosed herein, wherein each solid form can be uniquely identified by several different analytical parameters, alone or in combination, such as, but not limited to powder X-ray diffraction pattern peaks or combinations of two or more peaks; single crystal X-ray diffraction pattern; solid state NMR 13 C chemical shifts or combinations of two or more chemical shifts; solid state NMR 19 F chemical shifts; Thermogravimetric Infra-red Analysis (TGA-IR); and Modulated differential scanning calorimetry (mDSC).
  • Fig. 1 is a PXRD pattern of Form 1.
  • Fig. 2 is a PXRD pattern of Form 5.
  • Fig. 3 is a PXRD pattern of the cyclopentyl methyl ether (CPME) solvate, Form 9.
  • Fig. 4 is a PXRD pattern of amorphous free form, Form 10.
  • Fig. 5 is a PXRD of the isopropyl acetate solvate, Form 11.
  • Fig. 6 is a PXRD pattern of the 750 mg/g spray dried dispersion (SDD).
  • Fig. 7 is an ORTEP diagram drawn with displacement parameters at 50% for the Form 1 asymmetric unit.
  • Fig. 8 is the calculated Form 1 PXRD pattern derived from the single crystal (SXRD) data.
  • Fig. 9 is an ORTEP diagram drawn with displacement parameters at 50% for the Form 5 asymmetric unit.
  • Fig. 10 is a calculated PXRD pattern of Form 5 anhydrous free form.
  • Fig. 11 is an ORTEP diagram drawn with displacement parameters at 50% for the CPME solvate, Form 8 asymmetric unit.
  • Fig. 12 is a calculated PXRD pattern of the CPME solvate, Form 8.
  • Fig. 13 is an ORTEP diagram drawn with displacement parameters at 50% for the isopropyl acetate solvate, Form 12 asymmetric unit.
  • Fig. 14 is a calculated PXRD pattern of the isopropyl acetate solvate, Form 12.
  • Fig. 15 is a 13 C solid-state NMR spectrum of Form 1 and the peaks marked by hashes are spinning side bands.
  • Fig. 16 is a 19 F solid-state NMR spectrum of Form 1 and the peaks marked by hashes are spinning side bands.
  • Fig. 17 is a 13 C solid-state NMR spectrum of Form 5 and the peaks marked by hashes are spinning side bands.
  • Fig. 18 is a 19 F solid-state NMR spectrum of Form 5 and the peaks marked by hashes are spinning side bands.
  • Fig. 19 is a 13 C solid-state NMR spectrum of CPME solvate Form 9 and the peaks marked by hashes are spinning side bands.
  • Fig. 20 is a 19 F solid-state NMR spectrum of CPME solvate Form 9 and the peaks marked by hashes are spinning side bands.
  • Fig. 21 is a 13 C solid-state NMR spectrum of amorphous free form, Form 10 and the peaks marked by hashes are spinning side bands.
  • Fig. 22 is a 19 F solid-state NMR spectrum of amorphous free form, Form 10 and the peaks marked by hashes are spinning side bands.
  • Fig. 23 is a 13 C solid-state NMR spectrum of the isopropyl acetate solvate Form 11 and the peaks marked by hashes are spinning side bands.
  • Fig. 24 is a 19 F solid-state NMR spectrum of the isopropyl acetate solvate Form 11 and the peaks marked by hashes are spinning side bands.
  • Fig. 25 is a 13 C solid-state NMR spectrum of the 750 mg/g spray dried dispersion (SDD).
  • Fig. 26 is a 19 F solid-state NMR spectrum of the 750 mg/g SDD and the peaks marked by hashes are spinning side bands.
  • Fig. 27 is a thermal gravimetric infrared analysis (TGA-IR) thermogram of the CPME solvate Form 9.
  • Fig. 28 is a Gram-Schmidt and IR of the CPME solvate, Form 9 (TGA-IR) at 9.056 min.
  • Fig. 29 is an overlay of IR spectra of the CPME solvate, Form 9 (top) and cyclopentyl methyl ether solvent (bottom).
  • Fig. 30 is a thermal gravimetric infrared analysis (TGA-IR) thermogram of the isopropyl acetate solvate, Form 11 .
  • Fig. 31 is a Gram-Schmidt and IR of the isopropyl acetate solvate, Form 11 (TGA-IR) at 10.321 min.
  • Fig. 32 is an overlay of IR spectra of the isopropyl acetate solvate, Form 11 (top) and isopropyl acetate solvent (bottom).
  • Fig. 33 is modulated differential scanning calorimetry (DSC) data of Form 10 amorphous free form, showing a glass transition temperature (Tg) of about 95 °C.
  • Fig. 34 is modulated DSC data of the 750 mg/g spray dried dispersion (SDD), showing a Tg of about 92 °C.
  • Fig. 35 is partial asymmetric unit diagram with representative labeling scheme and anisotropic displacement parameters drawn at 50% probability for Form 14.
  • Fig. 36 is a calculated powder pattern of N-(Methoxycarbonyl)-3-methyl-L-valyl-(4R)-N- ⁇ (1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide, ethyl acetate solvate, Form 14.
  • Figure 37 is a PXRD pattern of N-(Methoxycarbonyl)-3-methyl-L-valyl-(4R)-N- ⁇ (1S)-1- cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide, Form 22.
  • Figure 38 is a PXRD pattern of N-(Methoxycarbonyl)-3-methyl-L-valyl-(4R)-N- ⁇ (1S)-1- cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide, Form 22 with peak picking for peaks over 3% relative intensity.
  • Figure 39 is an ORTEP diagram (color) drawn with displacement parameters at 50% for N-(Methoxycarbonyl)-3-methyl-L-valyl-(4R)-N- ⁇ (1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide, Form 22 asymmetric unit.
  • Figure 40 is an overlay of powder pattern obtained for N-(Methoxycarbonyl)-3-methyl-L- valyl-(4R)-N- ⁇ (1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L- prolinamide, Form 22 (bottom) and calculated powder pattern from single crystal data (top).
  • Figure 41 is a 13 C solid-state NMR spectrum of N-(Methoxycarbonyl)-3-methyl-L-valyl- (4R)-N- ⁇ (1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L- prolinamide, Form 22 - the peaks marked by hashes are spinning side bands.
  • Figure 42 is an 19 F solid-state NMR spectrum of N-(Methoxycarbonyl)-3-methyl-L-valyl- (4R)-N- ⁇ (1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L- prolinamide Form 22.
  • the peaks marked by hashes are spinning side bands.
  • the present disclosure describes forms of an anhydrous crystalline form of /V- (Methoxycarbonyl)-3-methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide which are designated herein as Form 1 and Form 5, respectively.
  • Form 1 is a particularly advantageous form of anhydrous crystalline form of /V-(Methoxycarbonyl)-3-methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)- 2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide which exhibits good stability and a lack of hygroscopicity and therefore is suitable for use in pharmaceutical compositions.
  • Form 22 is also a particularly advantageous form of anhydrous crystalline form of /V-(Methoxycarbonyl)-3-methyl-L-valyl-(4 ?)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)- 2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide which exhibits good stability and a lack of hygroscopicity and therefore is suitable for use in pharmaceutical compositions.
  • Both Form 1 and Form 22 are non-solvated (ansolvate) forms of the compound.
  • the present disclosure also describes amorphous /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4F?)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide and solid forms of /V-(Methoxycarbonyl)-3-methyl-L-valyl- (4F?)-/V- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L- prolinamide, cyclopentyl methyl ether solvate, /V-(Methoxycarbonyl)-3-methyl-L-valyl- (4F?)-/V- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl
  • the following embodiments of the invention are designated as E1 to E.
  • E1 is a compound which is an anhydrous crystalline form of /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4F?)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide.
  • E2 is the compound of E1 which is anhydrous crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4F?)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide, Form 1 characterized by a 13 C solid state NMR peak at 50.8 ppm ⁇ 0.2 ppm.
  • E3 is the compound of E1 which is anhydrous crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4F?)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide, Form 1 characterized by 13 C solid state NMR peaks at
  • E4 is the compound of E1 which is anhydrous crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide, Form 1 characterized by 13 C solid state NMR peaks at
  • E5 is the compound of E1 which is anhydrous crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide, Form 1 characterized by 13 C solid state NMR peaks at
  • E6 is the compound of E1 which is anhydrous crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide, Form 1 characterized by a 13 C solid state NMR peak at
  • E7 is the compound of E1 which is anhydrous crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide, Form 1 characterized by 13 C solid state NMR peaks at
  • E8 is the compound of E1 which is anhydrous crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide, Form 1 characterized by 13 C solid state NMR peaks at
  • each peak is ⁇ 0.2 ppm and a 19 F solid state NMR peak at -70.7 ppm ⁇ 0.2 ppm.
  • E9 is the compound of E1 which is anhydrous crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide, Form 1 characterized by 13 C solid state NMR peaks at
  • E10 is the compound of E1 which is anhydrous crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide, Form 1 characterized by a 13 C solid state NMR peak at
  • E11 is the compound of E1 which is anhydrous crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide, Form 1 characterized by 13 C solid state NMR peaks at
  • each peak is ⁇ 0.2 ppm and one to four powder X-ray diffraction peaks (Cu Ka radiation) selected from the group consisting of peaks at 9.1 , 9.6, 10.3 and 16.2 degrees 20 wherein each peak is ⁇ 0.2 degrees 20.
  • E12 is the compound of E1 which is anhydrous crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide, Form 1 characterized by 13 C solid state NMR peaks at
  • each peak is ⁇ 0.2 ppm and one to four powder X-ray diffraction peaks (Cu Ka radiation) selected from the group consisting of peaks at 9.1 , 9.6, 10.3 and 16.2 degrees 20 wherein each peak is ⁇ 0.2 degrees 20.
  • E13 is the compound of E1 which is anhydrous crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide, Form 1 characterized by 13 C solid state NMR peaks at
  • each peak is ⁇ 0.2 ppm and one to four powder X-ray diffraction peaks (Cu Ka radiation) selected from the group consisting of peaks at 9.1 , 9.6, 10.3 and 16.2 degrees 20 wherein each peak is ⁇ 0.2 degrees 20.
  • E14 is the compound of E1 which is anhydrous crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide, Form 1 characterized by a 13 C solid state NMR peak at
  • E15 is the compound of E1 which is anhydrous crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide, Form 1 characterized by 13 C solid state NMR peaks at
  • each peak is ⁇ 0.2 ppm, a 19 F solid state NMR peak at -70.7 ppm ⁇ 0.2 ppm and one to four powder X-ray diffraction peaks (Cu Ka radiation) selected from the group consisting of peaks at 9.1 , 9.6, 10.3 and 16.2 degrees 20 wherein each peak is ⁇ 0.2 degrees 20.
  • E16 is the compound of E1 which is anhydrous crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide, Form 1 characterized by 13 C solid state NMR peaks at 50.8 ppm and 43.5 ppm wherein each peak is ⁇ 0.2 ppm, a 19 F solid state NMR peak at -70.7 ppm ⁇ 0.2 ppm and one to four powder X-ray diffraction peaks (Cu Ka radiation) selected from the group consisting of peaks at 9.1 , 9.6, 10.3 and 16.2 degrees 20 wherein each peak is ⁇ 0.2 degrees 20.
  • Cu Ka radiation powder X-ray diffraction peaks
  • E17 is the compound of E1 which is anhydrous crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide, Form 1 characterized by 13 C solid state NMR peaks at 50.8 ppm, 58.3 ppm and 43.5 ppm wherein each peak is ⁇ 0.2 ppm, a 19 F solid state NMR peak at -70.7 ppm ⁇ 0.2 ppm and one to four powder X-ray diffraction peaks (Cu Ka radiation) selected from the group consisting of peaks at 9.1 , 9.6, 10.3 and 16.2 degrees 20 wherein each peak is ⁇ 0.2 degrees 20.
  • Cu Ka radiation powder X-ray diffraction peaks
  • E18 is /V-(Methoxycarbonyl)-3-methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide, Form 1 which is substantially pure.
  • E19 is the compound of E1 which is anhydrous crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxo pyrrolidin-3-yl]ethyl ⁇ -4-
  • E20 is the compound of claim 1 which is anhydrous crystalline /V-(Methoxycarbonyl)- 3-methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxo pyrrolidin-3-yl]ethyl ⁇ -4-
  • E21 is the compound of E1 which is anhydrous crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxo pyrrolidin-3-yl]ethyl ⁇ -4-
  • E22 is a solid form of /V-(Methoxycarbonyl)-3-methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2- [(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide, comprising Form 1 according to any one of E2 to E21 and wherein the solid form comprises less than 95%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 3%, or less than 1 % by weight of any other solid form or solid forms of the compound /V- (Methoxycarbonyl)-3-methyl-L-valyl
  • E23 is the solid form of E22 wherein the solid form comprises less than 10% by weight of any other solid form or solid forms of /V-(Methoxycarbonyl)-3-methyl-L-valyl-(4F?)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide.
  • E24 is the solid form of E22 which comprises less than 5% by weight of any other solid form or solid forms of /V-(Methoxycarbonyl)-3-methyl-L-valyl-(4 ?)-/ ⁇ /- ⁇ (1 S)-1-cyano- 2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide.
  • E25 is the solid form of E22 which comprises less than 2% by weight of any other solid form or solid forms of /V-(Methoxycarbonyl)-3-methyl-L-valyl-(4 ?)-/ ⁇ /- ⁇ (1 S)-1-cyano- 2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide.
  • E26 is the solid form of E22 which comprises less than 1% by weight of any other solid form or solid forms of /V-(Methoxycarbonyl)-3-methyl-L-valyl-(4 ?)-/ ⁇ /- ⁇ (1 S)-1-cyano- 2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide.
  • E27 is the solid form of any one of E22 to E26 wherein the other solid form or solid forms are selected from Form 5, Form 10, and Form 5 and Form 10.
  • E28 is a pharmaceutical composition comprising a therapeutically effective amount of Form 1 according to any one of E2 to E21 or of the solid form of any one of E22 to E27 and a pharmaceutically acceptable carrier.
  • E29 is the pharmaceutical composition of E28 comprising 100 mg to 1000 mg of Form 1.
  • E30 is the pharmaceutical composition of E29 comprising 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg 800 mg, 900 mg or 1000 mg of Form 1.
  • E31 is the pharmaceutical composition of E29 comprising 300 mg to 600 mg of Form 1.
  • E32 is a method of treating a coronavirus infection in a patient the method comprising administering a therapeutically effective amount of anhydrous crystalline /V- (Methoxycarbonyl)-3-methyl-L-valyl-(4F?)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxo pyrrolidin-3- yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide, Form 1 according to any one any one of claims 2 to 21 or the solid form of any one of E22 to E26 to a patient in need thereof.
  • anhydrous crystalline /V- (Methoxycarbonyl)-3-methyl-L-valyl-(4F?)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxo pyrrolidin-3- yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide Form 1 according to any one any
  • E33 is a method of treating a coronavirus infection in a patient the method comprising administering a pharmaceutical composition according to any one of E28 to E31.
  • E34 is the method of E32 or E33 wherein the coronavirus infection is a SARS-CoV-2 infection.
  • E35 is anhydrous crystalline /V-(Methoxycarbonyl)-3-methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1- cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide, Form 1 according to any one of E2 to E21 for use in the treatment of a coronavirus infection.
  • E36 is a pharmaceutical composition according to any one of E28 to E31 for use in the treatment of a coronavirus infection.
  • E37 is the use of E35 or E36 wherein the coronavirus infection is a SARS-CoV-2 infection.
  • E38 is the compound of E1 which is anhydrous crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide, Form 5 characterized by 19 F solid state NMR peaks at -
  • E39 is the compound of E1 which is anhydrous crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide, Form 5 characterized by 19 F solid state NMR peaks at -
  • E40 is the compound of E1 which is anhydrous crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide, Form 5 characterized by 19 F solid state NMR peaks at -
  • E41 is the compound of E1 which is anhydrous crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide, Form 5 characterized by 19 F solid state NMR peaks at -
  • E42 is the compound of E1 which is anhydrous crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide, Form 5 characterized by 19 F solid state NMR peaks at -
  • E43 is the compound of E1 which is anhydrous crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide, Form 5 characterized by 19 F solid state NMR peaks at -
  • E44 is the compound of E1 which is anhydrous crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide, Form 5 characterized by 19 F solid state NMR peaks at -
  • E45 is the compound of E1 which is anhydrous crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide, Form 5 characterized by 19 F solid state NMR peaks at -
  • E46 is the compound of E1 which is anhydrous crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide, Form 5 characterized by 19 F solid state NMR peaks at -
  • E47 is the compound of E1 which is anhydrous crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide, Form 5 characterized by 19 F solid state NMR peaks at -
  • E49 is the compound of E1 which is anhydrous crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxo pyrrolidin-3-yl]ethyl ⁇ -4-
  • E50 is /V-(Methoxycarbonyl)-3-methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide, Form 5 which is substantially pure.
  • E51 is a solid form of /V-(Methoxycarbonyl)-3-methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2- [(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide, comprising Form 5 and wherein the solid form comprises less than 95%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 3%, or less than 1 % by weight of any other solid forms of the compound /V-(Methoxycarbonyl)-3-methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide.
  • E52 is the solid form of E51 wherein the other solid form or solid forms are selected from Form 1 , Form 10, and Form 1 and Form 10.
  • E53 is a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of anhydrous crystalline /V-(Methoxycarbonyl)-3-methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2- [(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide, Form 5 according to any one of E38 to E50 and a pharmaceutically acceptable carrier.
  • E54 is a method of treating a coronavirus infection in a patient the method comprising administering a therapeutically effective amount of anhydrous crystalline /V- (Methoxycarbonyl)-3-methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxo pyrrolidin-3- yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide, Form 5 according to any one of E38 to E50 to a patient in need thereof.
  • anhydrous crystalline /V- (Methoxycarbonyl)-3-methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxo pyrrolidin-3- yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide Form 5 according to any one of E38 to E50 to a patient in need thereof.
  • E55 is a method of treating a coronavirus infection in a patient the method comprising administering a pharmaceutical composition according to E53.
  • E56 is the method of E54 or E55 wherein the coronavirus infection is a SARS-CoV-2 infection.
  • E57 is anhydrous crystalline /V-(Methoxycarbonyl)-3-methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1- cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide, Form 5 according to any one of E38 to E50 for use in the treatment of a coronavirus infection.
  • E58 is a pharmaceutical composition according to E53 for use in the treatment of a coronavirus infection.
  • E59 is the use of E57 or E58 wherein the coronavirus infection is a SARS-CoV-2 infection.
  • E60 is crystalline /V-(Methoxycarbonyl)-3-methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2- [(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide, cyclopentyl methyl ether solvate.
  • E62 is the compound of E60 which is crystalline /V-(Methoxycarbonyl)-3-methyl-L- valyl-(4R)-/V- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L- prolinamide, cyclopentyl methyl ether solvate, Form 8 characterized by an ORTEP diagram drawn with displacement parameters at 50% for the Form 8 asymmetric unit which is substantially the same to that in Fig. 11.
  • E63 is the compound of E60 which is crystalline /V-(Methoxycarbonyl)-3-methyl-L- valyl-(4R)-/V- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L- prolinamide, cyclopentyl methyl ether solvate, Form 9 characterized by 19 F solid state NMR peaks at -70.2 ppm and -70.5 ppm wherein each peak is ⁇ 0.2 ppm and one to three 13 C solid state NMR peaks selected from the group of peaks at 32.7 ppm, 24.2 ppm and 56.0 ppm wherein each peak is ⁇ 0.2 ppm.
  • E64 is the compound of E60 which is crystalline /V-(Methoxycarbonyl)-3-methyl-L- valyl-(4R)-/V- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L- prolinamide, cyclopentyl methyl ether solvate, Form 9 characterized by 19 F solid state NMR peaks at -70.2 ppm and -70.5 ppm wherein each peak is ⁇ 0.2 ppm and one to three powder X-ray diffraction peaks (Cu Ka radiation) selected from peaks at 7.1 , 7.9 and 19.8 degrees 20 wherein each peak is ⁇ 0.2 degrees 20.
  • E65 is the compound of E60 which is crystalline /V-(Methoxycarbonyl)-3-methyl-L- valyl-(4R)-/V- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L- prolinamide, cyclopentyl methyl ether solvate, Form 9 characterized by one to three 13 C solid state NMR peaks selected from the group of peaks at 32.7 ppm, 24.2 ppm and 56.0 ppm wherein each peak is ⁇ 0.2 ppm and one to three powder X-ray diffraction peaks (Cu Ka radiation) selected from peaks at 7.1 , 7.9 and 19.8 degrees 20 wherein each peak is ⁇ 0.2 degrees 20.
  • Cu Ka radiation powder X-ray diffraction peaks
  • E66 is the compound of E60 which is crystalline /V-(Methoxycarbonyl)-3-methyl-L- valyl-(4R)-/V- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L- prolinamide, cyclopentyl methyl ether solvate, Form 9 characterized by 19 F solid state NMR peaks at -70.2 ppm and -70.5 ppm wherein each peak is ⁇ 0.2 ppm, one to three 13 C solid state NMR peaks selected from the group of peaks at 32.7 ppm, 24.2 ppm and 56.0 ppm wherein each peak is ⁇ 0.2 ppm and one to three powder X-ray diffraction peaks (Cu Ka radiation) selected from peaks at 7.1 , 7.9 and 19.8 degrees 20 wherein each peak is ⁇ 0.2 degrees 20.
  • E67 is the compound according to E60 which is crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide, cyclopentyl methyl ether solvate, Form 9 characterized by 19 F solid state NMR peaks at -70.2 ppm and -70.5 ppm wherein each peak is ⁇ 0.2 ppm.
  • E68 is the compound according to E60 which is crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide, cyclopentyl methyl ether solvate, Form 9 characterized by one to three 13 C solid state NMR peaks selected from the group of peaks at 32.7 ppm, 24.2 ppm and 56.0 ppm wherein each peak is ⁇ 0.2 ppm.
  • E69 is crystalline /V-(Methoxycarbonyl)-3-methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2- [(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide, isopropyl acetate solvate, Form 11.
  • E70 is the compound according to E69 characterized by a 13 C solid state NMR peak at 20.9 ppm ⁇ 0.2 ppm.
  • E71 is the compound according to E69 characterized by 19 F solid state NMR peaks at -69.8 ppm, -71.9 ppm and -72.4 ppm wherein each peak is ⁇ 0.2 ppm.
  • E72 is the compound according to E69 characterized by 13 C solid state NMR peaks at 20.9 ppm ⁇ 0.2 ppm, 38.7 ppm ⁇ 0.2 ppm and 52.0 ppm ⁇ 0.2 ppm.
  • E73 is the compound according to E69 characterized by 19 F solid state NMR peaks at -69.8 ppm, -71.9 ppm and -72.4 ppm wherein each peak is ⁇ 0.2 ppm, and a 13 C solid state NMR peak at 20.9 ppm ⁇ 0.2 ppm.
  • E74 is the compound according to E69 characterized by 19 F solid state NMR peaks at -69.8 ppm, -71.9 ppm and -72.4 ppm wherein each peak is ⁇ 0.2 ppm, and one to three 13 C solid state NMR peaks selected from the group of peaks at 20.9 ppm ⁇ 0.2 ppm, 38.7 ppm ⁇ 0.2 ppm and 52.0 ppm ⁇ 0.2 ppm.
  • E75 is the compound according to E69 characterized by 19 F solid state NMR peaks at -69.8 ppm, -71.9 ppm and -72.4 ppm wherein each peak is ⁇ 0.2 ppm, and one to four powder X-ray diffraction peaks (Cu Ka radiation) selected from the group of peaks at 8.5, 6.3, 10.7, and 19.1 degrees 20 wherein each peak is ⁇ 0.2 degrees 20.
  • E76 is the compound according to E69 characterized by 19 F solid state NMR peaks at -69.8 ppm, -71.9 ppm and -72.4 ppm wherein each peak is ⁇ 0.2 ppm, a 13 C solid state NMR peak at 20.9 ppm ⁇ 0.2 ppm and one to four powder X-ray diffraction peaks (Cu Ka radiation) selected from the group of peaks at 8.5, 6.3, 10.7, and 19.1 degrees 20 wherein each peak is ⁇ 0.2 degrees 20.
  • E77 is the compound according to E69 characterized by 19 F solid state NMR peaks at -69.8 ppm, -71.9 ppm and -72.4 ppm wherein each peak is ⁇ 0.2 ppm, one to three 13 C solid state NMR peaks selected from the group of peaks at 20.9 ppm ⁇ 0.2 ppm, 38.7 ppm ⁇ 0.2 ppm and 52.0 ppm ⁇ 0.2 ppm and one to four powder X-ray diffraction peaks (Cu Ka radiation) selected from the group of peaks at 8.5, 6.3, 10.7, and 19.1 degrees 20 wherein each peak is ⁇ 0.2 degrees 20.
  • Cu Ka radiation powder X-ray diffraction peaks
  • E78 is the compound according to E69 characterized by a 13 C solid state NMR peak at 20.9 ppm ⁇ 0.2 ppm, and one to four powder X-ray diffraction peaks (Cu Ka radiation) selected from the group of peaks at 8.5, 6.3, 10.7, and 19.1 degrees 20 wherein each peak is ⁇ 0.2 degrees 20.
  • E79 is the compound according to E69 characterized by 13 C solid state NMR peaks at 20.9 ppm ⁇ 0.2 ppm, 38.7 ppm ⁇ 0.2 ppm and 52.0 ppm ⁇ 0.2 ppm and one to four powder X-ray diffraction peaks (Cu Ka radiation) selected from the group of peaks at 8.5, 6.3, 10.7 and 19.1 degrees 20 wherein each peak is ⁇ 0.2 degrees 20.
  • E80 is a spray dried dispersion comprising /V-(Methoxycarbonyl)-3-methyl-L-valyl- (4R)-/V- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L- prolinamide and a pharmaceutically acceptable excipient.
  • E81 is the spray dried dispersion according to E80 comprising amorphous /V- (Methoxycarbonyl)-3-methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide.
  • E82 is the spray dried dispersion according to E81 comprising hydroxypropyl methylcellulose acetate succinate - M grade.
  • E83 is the spray dried dispersion according to E82 consisting of 750 mg/g of amorphous /V-(Methoxycarbonyl)-3-methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide and 250 mg/g of hydroxypropyl methylcellulose acetate succinate - M grade.
  • E84 is a pharmaceutical composition comprising the spray dried dispersion of any one of E80 to E83.
  • E85 is a method of treating a coronavirus infection in a patient the method comprising administering a therapeutically effective amount of a pharmaceutical composition according to E84 to a patient in need thereof.
  • E86 is the method of E85 wherein the coronavirus infection is a SARS-CoV-2 infection.
  • E87 is crystalline /V-(Methoxycarbonyl)-3-methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2- [(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide, ethyl acetate solvate, Form 14.
  • E89 is the compound according to E87 which is crystalline /V-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide, ethyl acetate solvate, Form 14 characterized by an ORTEP diagram drawn with displacement parameters at 50% for the Form 14 asymmetric unit which is substantially the same to that in Fig. 35.
  • E90 is crystalline /V-(Methoxycarbonyl)-3-methyl-L-valyl-(4R)-/ ⁇ /- ⁇ (1 S)-1-cyano-2- [(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide, Form 22.
  • E91 is the compound according to E90 characterized by 19 F solid state NMR peaks at -71.0 and -71.5 ppm, each ⁇ 0.2 ppm.
  • E92 is the compound according to E90 characterized by one to three 13 C solid state NMR peaks selected from the group of peaks at 53.3 ppm, 39.8 ppm and 169.1 ppm wherein each peak is ⁇ 0.2 ppm.
  • E93 is the compound according to E90 characterized by 19 F solid state NMR peaks at -71.0 and -71.5 ppm, each ⁇ 0.2 ppm and one to four 13 C solid state NMR peaks selected from the group of peaks at 53.3 ppm, 39.8 ppm, 169.1 ppm and 40.8 ppm, wherein each peak is ⁇ 0.2 ppm.
  • E94 is the compound according to E90 characterized by 19 F solid state NMR peaks at -71.0 ppm and -71.5 ppm wherein each peak is ⁇ 0.2 ppm, and one to two powder X- ray diffraction peaks (Cu Ka radiation) selected from peaks at 11.6 and 14.6 degrees 20 wherein each peak is ⁇ 0.2 degrees 20.
  • E95 is the compound according to E90 characterized by one to three 13 C solid state NMR peaks selected from the group of peaks at 53.3 ppm, 39.8 ppm and 169.1 ppm wherein each peak is ⁇ 0.2 ppm, and one to two powder X-ray diffraction peaks (Cu Ka radiation) selected from peaks at 11.6 and 14.6 degrees 20 wherein each peak is ⁇ 0.2 degrees 20.
  • E96 is the compound according to E90 characterized by 19 F solid state NMR peaks at -71.0 ppm and -71.5 ppm wherein each peak is ⁇ 0.2 ppm, one to four 13 C solid state NMR peaks selected from the group of peaks at 53.3 ppm, 39.8 ppm, 169.1 ppm and 40.8 ppm wherein each peak is ⁇ 0.2 ppm, and one to two powder X-ray diffraction peaks (Cu Ka radiation) selected from peaks at 11.6 and 14.6 degrees 20 wherein each peak is ⁇ 0.2 degrees 20.
  • the present invention contemplates that the individual solid forms of the compounds of the invention can exist in the presence of other solid forms of the compounds of the invention.
  • Form 1 can exist in the presence of the any other of the solid forms described herein (e.g., Forms 5, 8, 9, 10, 11 , 12, 14 or 22) or mixtures thereof.
  • the present invention contemplates that Form 1 can exist in the presence of the any other of the solid forms (e.g. Forms 5, 8, 9, 10, 11 , 12, 14 or 22) or mixtures thereof.
  • the present invention provides Form 1 , wherein Form 1 is present in a solid form that includes less than 95%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 3%, or less than 1 % by weight of any other physical forms of the compound of Formula I.
  • a solid form of the compound of Formula I comprising Form 1 that has any one of the powder X-ray diffraction patterns, NMR spectra described above, wherein said solid form includes less than 95%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 3%, or less than 1 % by weight of any other physical forms of the compound of Formula I.
  • the present invention relates to Form 1 , wherein said form is substantially pure crystalline form.
  • the present invention contemplates that Form 22 can exist in the presence of the any other of the solid forms (e.g. Forms 5, 8, 9, 10, 11 , 12, 14 or 1) or mixtures thereof. Accordingly, in one embodiment, the present invention provides Form 1 , wherein Form 1 is present in a solid form that includes less than 95%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 3%, or less than 1 % by weight of any other physical forms of the compound of Formula I.
  • a solid form of the compound of Formula I comprising Form 1 that has any one of the powder X-ray diffraction patterns, NMR spectra described above, wherein said solid form includes less than 95%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 3%, or less than 1 % by weight of any other physical forms of the compound of Formula I.
  • the present invention relates to Form 22, wherein said form is substantially pure crystalline form.
  • the present invention contemplates that one of Forms 5, 8, 9, 10, 11 , 12 or 14 can exist in the presence of any other of the solid forms of the compound of Formula I or mixtures thereof. Accordingly, in one embodiment, the present invention provides one of Forms 5, 8, 9, 10, 11 , 12 or 14 , wherein said Form is present in a solid form that includes less than 95%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 3%, or less than 1 % by weight of any other physical forms of the compound of Formula I .
  • a solid form of the compound of Formula I comprising Form 12 that has any one of the powder X-ray diffraction patterns, NMR spectra described above, wherein said solid form includes less than 95%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 3%, or less than 1% by weight of any other physical forms of the compound of Formula I.
  • the present invention relates to any one of Forms 5, 8, 9, 10, 11 , 12 and 14, wherein said form is a substantially pure form.
  • the invention comprises pharmaceutical compositions.
  • a “pharmaceutical composition” refers to a mixture of one or more of the compounds of the invention and one or more pharmaceutically acceptable excipient.
  • excipient is used herein to describe any ingredient other than the compound(s) of the invention.
  • excipient will to a large extent depend on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • excipient includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, carriers, diluents and the like that are physiologically compatible.
  • excipients include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof, and may include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol, or sorbitol in the composition.
  • excipients also include various organic solvents (such as hydrates and solvates).
  • the pharmaceutical compositions may, if desired, contain additional excipients such as flavorings, binders/binding agents, lubricating agents, disintegrants, sweetening or flavoring agents, coloring matters or dyes, and the like.
  • excipients such as citric acid
  • disintegrants such as starch, alginic acid and certain complex silicates
  • binding agents such as sucrose, gelatin and acacia.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes.
  • Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules.
  • excipients therefore, also include lactose or milk sugar and high molecular weight polyethylene glycols.
  • the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with additional excipients such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
  • excipients also include pharmaceutically acceptable substances such as wetting agents or minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives, or buffers, which enhance the shelf life or effectiveness of the compound.
  • compositions of this invention may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable, and infusible solutions), dispersions or suspensions, tablets, capsules, pills, powders, liposomes, and suppositories.
  • liquid solutions e.g., injectable, and infusible solutions
  • dispersions or suspensions tablets, capsules, pills, powders, liposomes, and suppositories.
  • the form depends on the intended mode of administration and therapeutic application.
  • compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with antibodies in general.
  • One mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular).
  • the compound is administered by intravenous infusion or injection.
  • the compound is administered by intramuscular or subcutaneous injection.
  • Oral administration of a solid dose form may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the invention.
  • the oral administration may be in a powder or granule form.
  • the oral dose form is sub-lingual, such as, for example, a lozenge.
  • the compounds of the invention are ordinarily combined with one or more adjuvants.
  • Such capsules or tablets may contain a controlled release formulation.
  • the dosage forms also may comprise buffering agents or may be prepared with enteric coatings.
  • oral administration may be in a liquid dose form.
  • Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water).
  • Such compositions also may comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents.
  • the invention comprises a parenteral dose form.
  • Parenteral administration includes, for example, subcutaneous injections, intravenous injections, intraperitoneally, intramuscular injections, intrasternal injections, and infusion.
  • injectable preparations i.e. , sterile injectable aqueous or oleaginous suspensions
  • suitable dispersing, wetting agents, and/or suspending agents may be formulated according to the known art using suitable dispersing, wetting agents, and/or suspending agents.
  • the invention comprises a topical dose form.
  • Topical administration includes, for example, transdermal administration, such as via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration.
  • Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams.
  • a topical formulation may include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of this invention are administered by a transdermal device, administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used.
  • Typical excipients include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
  • Penetration enhancers may be incorporated - see, for example, B. C. Finnin, and T. M. Morgan, J. Pharm. Sci. , vol. 88, pp. 955-958, 1999.
  • Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of this invention is dissolved or suspended in a suitable excipient.
  • a typical formulation suitable for ocular or aural administration may be in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments, biodegradable (i.e. , absorbable gel sponges, collagen) and non- biodegradable (i.e., silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • a polymer such as crossed linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
  • a preservative such as benzalkonium chloride.
  • Such formulations may also be delivered by iontophoresis.
  • the compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant.
  • Formulations suitable for intranasal administration are typically administered in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1 , 1,1, 2, 3,3,3- heptafluoropropane.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the invention comprises a rectal dose form.
  • rectal dose form may be in the form of, for example, a suppository. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • compositions of the invention may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures.
  • effective formulations and administration procedures are well known in the art and are described in standard textbooks.
  • Formulation of drugs is discussed in, for example, Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,
  • Acceptable excipients are nontoxic to recipients at the dosages and concentrations employed, and may comprise buffers such as phosphate, citrate, and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or Igs; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine,
  • compositions may be provided in the form of tablets or capsules containing 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250,300, 350, 400, 450, 500, 600, 750 or 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, or in another embodiment, from about 1 mg to about 100 mg of active ingredient or from 50 to 500 milligrams. Intravenously, doses may range from about
  • Liposomes containing compounds of the invention may be prepared by methods known in the art, such as described in U.S. Pat. Nos. 4,485,045 and 4,544,545. Liposomes with enhanced circulation time are disclosed in U.S. Patent No. 5,013,556. Particularly useful liposomes can be generated by the reverse phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol and PEG- derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter.
  • PEG-PE PEG- derivatized phosphatidylethanolamine
  • microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • sustained-release preparations may be used. Suitable examples of sustained- release preparations include semi-permeable matrices of solid hydrophobic polymers containing a compound of the invention, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or 'poly(vinylalcohol)), polylactides (U.S. Pat. No.
  • copolymers of L-glutamic acid and 7 ethyl-L-glutamate copolymers of L-glutamic acid and 7 ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as those used in LUPRON DEPOTTM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid.
  • LUPRON DEPOTTM injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate
  • sucrose acetate isobutyrate sucrose acetate isobutyrate
  • poly-D-(-)-3-hydroxybutyric acid poly-D-(-)-3-hydroxybutyric acid.
  • the formulations to be used for intravenous administration must be sterile. This is readily accomplished by, for example, filtration through sterile filtration membranes.
  • Compounds of the invention are generally placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.
  • Suitable emulsions may be prepared using commercially available fat emulsions, such as IntralipidTM, LiposynTM, InfonutrolTM, LipofundinTM and LipiphysanTM.
  • the active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g., egg phospholipids, soybean phospholipids or soybean lecithin) and water.
  • an oil e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil
  • a phospholipid e.g., egg phospholipids, soybean phospholipids or soybean lecithin
  • other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emul
  • Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%.
  • the fat emulsion can comprise fat droplets between 0.1 and 1.0 pm, particularly 0.1 and 0.5 pm, and have a pH in the range of 5.5 to 8.0.
  • the emulsion compositions can be those prepared by mixing a compound of the invention with IntralipidTM or the components thereof (soybean oil, egg phospholipids, glycerol and water).
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulized by use of gases. Nebulized solutions may be breathed directly from the nebulizing device, or the nebulizing device may be attached to a face mask, tent or intermittent positive pressure breathing machine.
  • Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
  • treating embraces both preventative, i.e., prophylactic, and palliative treatment, i.e., relieve, alleviate, or slow the progression of the patient’s disease (or condition) or any tissue damage associated with the disease.
  • the terms, “subject, “individual” or “patient,” used interchangeably, refer to any animal, including mammals. Mammals according to the invention include canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, humans and the like, and encompass mammals in utero. In an embodiment, humans are suitable subjects. Human subjects may be of any gender and at any stage of development.
  • the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician, which may include one or more of the following:
  • preventing the disease for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition, or disorder (i.e., arresting or slowing further development of the pathology and/or symptomatology); and
  • ameliorating the disease for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition, or disorder (i.e., reversing the pathology and/or symptomatology).
  • a compound of the invention is administered in an amount effective to treat a condition as described herein.
  • the compounds of the invention can be administered as compound per se, or alternatively, as a solvate thereof.
  • the compound per se or solvate thereof will simply be referred to as the compounds of the invention.
  • the compounds of the invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • the compounds of the invention may be administered orally, rectally, vaginally, parenterally, topically, intranasally, or by inhalation.
  • the compounds of the invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the bloodstream directly from the mouth.
  • the compounds of the invention may also be administered parenterally, for example directly into the bloodstream, into muscle, or into an internal organ.
  • suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.
  • the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • the compounds of the invention can also be administered intranasally or by inhalation.
  • the compounds of the invention may be administered rectally or vaginally.
  • the compounds of the invention may also be administered directly to the eye or ear.
  • the dosage regimen for the compounds of the invention and/or compositions containing said compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus, the dosage regimen may vary widely.
  • the total daily dose of a compound of the invention is typically from about 0.01 to about 100 mg/kg (i.e. , mg compound of the invention per kg body weight) for the treatment of the indicated conditions discussed herein.
  • total daily dose of the compound of the invention is from about 0.1 to about 50 mg/kg, and in another embodiment, from about 0.5 to about 30 mg/kg. It is not uncommon that the administration of the compounds of the invention will be repeated a plurality of times in a day (typically no greater than 4 times). Multiple doses per day typically may be used to increase the total daily dose, if desired.
  • the compounds of the invention inhibit viral proteases, particularly coronavirus viral proteases such as the 3CL (Mpro) protease of SARS-CoV-2 which is the causative virus of COVID-19.
  • the compounds of the invention may inhibit the activity of the main viral protease and may be useful in the treatment, prevention, suppression, and amelioration of viral infections including coronavirus infections such as SARS-CoV-2 infections and COVID-19.
  • the compounds of the invention may also be useful in the treatment or amelioration of sequelae of coronavirus infections such as use or treatment of long COVID.
  • the compounds of the invention can be used alone, or in combination with one or more other therapeutic agents.
  • the invention provides any of the uses, methods or compositions as defined herein wherein the compound of the invention is used in combination with one or more other therapeutic agent discussed herein.
  • the compounds of the present invention can be used in the methods of the invention in combination with other drugs.
  • a SARS-CoV-2 coronavirus- infected patient i.e., a patient with COVID-19
  • an interferon such as interferon alpha
  • a pegylated interferon such as PEG-lntron or Pegasus
  • Other additional agents that can be used in the methods of the present invention include dexamethasone, azithromycin and remdesivir.
  • Examples of greater clinical benefits could include a larger reduction in COVID-19 symptoms, a faster time to alleviation of symptoms, reduced lung pathology, a larger reduction in the amount of SARS-CoV-2 coronavirus in the patient (viral load), and decreased mortality.
  • the SARS-CoV-2 coronavirus infects cells which express P-glycoprotein.
  • Some of the SARS-CoV-2 coronavirus 3CL protease inhibitors of the invention may be P- glycoprotein substrates.
  • Compounds which inhibit the SARS-CoV-2 coronavirus which are also P-glycoprotein substrates may be dosed with a P-glycoprotein inhibitor.
  • P-glycoprotein inhibitors are verapamil, vinblastine, ketoconazole, nelfinavir, ritonavir, or cyclosporine.
  • the P-glycoprotein inhibitors act by inhibiting the efflux of the SARS-CoV-2 coronavirus inhibitors of the invention out of the cell.
  • the inhibition of the P-glycoprotein-based efflux will prevent reduction of intracellular concentrations of the SARS-CoV-2 coronavirus inhibitor due to P-glycoprotein efflux. Inhibition of the P-glycoprotein efflux will result in larger intracellular concentrations of the SARS-CoV-2 coronavirus inhibitors.
  • Dosing a SARS-CoV-2 coronavirus-infected patient with the SARS-CoV-2 coronavirus 3CL protease inhibitors of the invention and a P-glycoprotein inhibitor may lower the amount of SARS-CoV-2 coronavirus 3CL protease inhibitor required to achieve an efficacious dose by increasing the intracellular concentration of the SARS-CoV-2 coronavirus 3CL protease inhibitor.
  • agents that may be used to increase the exposure of a mammal to a compound of the present invention are those that can act as inhibitors of at least one isoform of the cytochrome P450 (CYP450) enzymes.
  • the isoforms of CYP450 that may be beneficially inhibited include, but are not limited to CYP1A2, CYP2D6, CYP2C9, CYP2C19 and CYP3A4.
  • the compounds used in the methods of the invention include compounds that may be CYP3A4 substrates and are metabolized by CYP3A4.
  • a SARS-CoV-2 coronavirus inhibitor which is a CYP3A4 substrate, such as SARS-CoV-2 coronavirus 3CL protease inhibitor, and a CYP3A4 inhibitor, such as ritonavir, nelfinavir or delavirdine will reduce the metabolism of the SARS-CoV-2 coronavirus inhibitor by CYP3A4. This will result in reduced clearance of the SARS-CoV-2 coronavirus inhibitor and increased SARS-CoV- 2 coronavirus inhibitor plasma concentrations. The reduced clearance and higher plasma concentrations may result in a lower efficacious dose of the SARS-CoV-2 coronavirus inhibitor.
  • Additional therapeutic agents that can be used in combination with the SARS-CoV-2 inhibitors in the methods of the present invention include the following:
  • PLpro inhibitors Apilomod, EIDD-2801, Ribavirin, Valganciclovir, /3-Thymidine, Aspartame, Oxprenolol, Doxycycline, Acetophenazine, lopromide, Riboflavin, Reproterol, 2,2'-Cyclocytidine, Chloramphenicol, Chlorphenesin carbamate, Levodropropizine, Cefamandole, Floxuridine, Tigecycline, Pemetrexed, L(+)-Ascorbic acid, Glutathione, Hesperetin, Ademetionine, Masoprocol, Isotretinoin, Dantrolene, Sulfasalazine Anti-bacterial, Silybin, Nicardipine, Sildenafil, Platycodin, Chrysin, Neohesperidin, Baicalin, Sugetriol-3,9-diacetate, (-)-Epigallocatechin gall
  • 3CLpro inhibitors Lymecycline, Chlorhexidine, Alfuzosin, Cilastatin, Famotidine, Almitrine, Progabide, Nepafenac, Carvedilol, Amprenavir, Tigecycline, Montelukast, Carminic acid, Mimosine, Flavin, Lutein, Cefpiramide, Phenethicillin, Candoxatril, Nicardipine, Estradiol valerate, Pioglitazone, Conivaptan, Telmisartan, Doxycycline, Oxytetracycline, (1 S,2R,4aS,5R,8aS)-1-Formamido-1 ,4a-dimethyl-6-methylene-5-((E)- 2-(2-oxo-2,5-dihydrofuran-3-yl)ethenyl)decahydronaphthalen-2-yl5-((R)-1,2-dithiolan-3- yl) pentan
  • RdRp inhibitors Valganciclovir, Chlorhexidine, Ceftibuten, Fenoterol, Fludarabine, Itraconazole, Cefuroxime, Atovaquone, Chenodeoxycholic acid, Cromolyn, Pancuronium bromide, Cortisone, Tibolone, Novobiocin, Silybin, Idarubicin Bromocriptine, Diphenoxylate, Benzylpenicilloyl G, Dabigatran etexilate, Betulonal, Gnidicin, 2/3,30/3-Dihydroxy-3,4-seco-friedelolactone-27-lactone, 14-Deoxy-11 ,12-didehydroandrographolide, Gniditrin, Theaflavin 3,3'-di-O-gallate, (R)- ((1R,5aS,6R,9aS)-1 ,5a-Dimethyl-7-methylene-3-oxo-6-((E)
  • Additional therapeutic agents that can be used in the methods of the invention include Diosmin, Hesperidin, MK-3207, Venetoclax, Dihydroergocristine, Bolazine, R428, Ditercalinium, Etoposide, Teniposide, UK-432097, Irinotecan, Lumacaftor, Velpatasvir, Eluxadoline, Ledipasvir, Lopinavir / Ritonavir + Ribavirin, Alferon, and prednisone.
  • Other additional agents useful in the methods of the present invention include dexamethasone, azithromycin and remdesivir as well as boceprevir, umifenovir and favipiravir.
  • RIG 1 pathway activators such as those described in US Patent No. 9,884,876.
  • protease inhibitors such as those described in Dai W, Zhang B, Jiang X-M, et al. Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease. Science. 2020;368(6497):1331- 1335 including compounds such as the compound shown below and a compound designated as DC402234
  • Another embodiment of the present invention is a method of treating COVID-19 in a patient wherein in addition to administering a compound of the present invention (i.e. Form 1 , Form 5, Form 8, Form 9, Form 10, Form 11 , Form 12 or Form 14) an additional agent is administered and the additional agent is selected from antivirals such as nirmatrelvir, remdesivir, galidesivir, favilavir/avifavir, molnupiravir (MK- 4482/EIDD 2801), AT-527, AT-301 , BLD-2660, favipiravir, camostat, SLV213 emtrictabine/tenofivir, clevudine, dalcetrapib, boceprevir, PBI-0451 , EDP-235 and ABX464, glucocorticoids such as dexamethasone and hydrocortisone, convalescent plasma, a recombinant human plasma such as gelsolin (Rhu-p65
  • SARS-CoV-2 inhibiting agent means any SARS-CoV-2-related coronavirus 3C-like protease inhibitor compound described herein which inhibits replication of SARS-CoV-2 in any manner.
  • SARS-CoV-2 SARS-CoV-2-related coronavirus
  • the term “interfering with or preventing” SARS-CoV-2-related coronavirus (“SARS-CoV-2”) viral replication in a cell means to reduce SARS-CoV-2 replication or production of SARS-CoV-2 components necessary for progeny virus in a cell treated with a compound of this invention as compared to a cell not being treated with a compound of this invention.
  • Simple and convenient assays to determine if SARS-CoV- 2 viral replication has been reduced include an ELISA assay for the presence, absence, or reduced presence of anti-SARS-CoV-2 antibodies in the blood of the subject (Nasoff, et al., PNAS 88:5462-5466, 1991), RT-PCR (Yu, et al., in Viral Hepatitis and Liver Disease 574-577, Nishioka, Suzuki and Mishiro (Eds.); Springer-Verlag, Tokyo, 1994). Such methods are well known to those of ordinary skill in the art.
  • total RNA from transduced and infected “control” cells can be isolated and subjected to analysis by dot blot or northern blot and probed with SARS-CoV-2-specific DNA to determine if SARS-CoV-2 replication is reduced.
  • reduction of SARS-CoV- 2 protein expression can also be used as an indicator of inhibition of SARS-CoV-2 replication. A greater than fifty percent reduction in SARS-CoV-2 replication as compared to control cells typically quantitates a prevention of SARS-CoV-2 replication.
  • the administration of two or more compounds “in combination” means that all of the compounds are administered closely enough in time to affect treatment of the subject.
  • the two or more compounds may be administered simultaneously or sequentially, via the same or different routes of administration, on same or different administration schedules and with or without specific time limits depending on the treatment regimen. Additionally, simultaneous administration may be carried out by mixing the compounds prior to administration or by administering the compounds at the same point in time but as separate dosage forms at the same or different site of administration.
  • a compound of the invention and the one or more other therapeutic agents may be administered as a fixed or non-fixed combination of the active ingredients.
  • the term "fixed combination” means a compound of the invention, or a pharmaceutically acceptable salt thereof, and the one or more therapeutic agents, are both administered to a subject simultaneously in a single composition or dosage.
  • the term “non-fixed combination” means that a compound of the invention, or a pharmaceutically acceptable salt thereof, and the one or more therapeutic agents are formulated as separate compositions or dosages such that they may be administered to a subject in need thereof simultaneously or sequentially with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the subject.
  • the compounds of this invention are administered in combination with additional therapeutic agents useful in treatment of viral infections including the pharmaceutically acceptable salts of the specifically named agents and the pharmaceutically acceptable solvates of said agents and salts.
  • agents and compounds of the invention can be combined with pharmaceutically acceptable vehicles such as saline, Ringer’s solution, dextrose solution, and the like.
  • pharmaceutically acceptable vehicles such as saline, Ringer’s solution, dextrose solution, and the like.
  • the particular dosage regimen, i.e. , dose, timing and repetition, will depend on the particular individual and that individual’s medical history.
  • kits comprising the compound of the invention or pharmaceutical compositions comprising the compound of the invention.
  • a kit may include, in addition to the compound of the invention or pharmaceutical composition thereof, diagnostic or therapeutic agents.
  • a kit may also include instructions for use in a diagnostic or therapeutic method.
  • the kit includes the compound or a pharmaceutical composition thereof and a diagnostic agent.
  • the kit includes the compound or a pharmaceutical composition thereof and one or more therapeutic agents, such as another antiviral agent such as nirmatrelvir, remdesivir or molnupiravir.
  • the invention comprises kits that are suitable for use in performing the methods of treatment described herein.
  • the kit contains a first dosage form comprising one or more of the compounds of the invention in quantities sufficient to carry out the methods of the invention.
  • the kit comprises one or more compounds of the invention in quantities sufficient to carry out the methods of the invention and a container for the dosage and a container for the dosage.
  • Powder X-Ray Diffraction was determined for N-(Methoxycarbonyl)-3-methyl-L- valyl-(4R)-N- ⁇ (1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L- prolinamide or solvate thereof (Forms 1 , 5, 9, 10, 11 and 750 mg/g SDD) according to the method below.
  • the divergence slit was set at 15 mm continuous illumination.
  • Diffracted radiation was detected by a PSD-Lynx Eye detector, with the detector PSD opening set at 4.11 degrees.
  • the X-ray tube voltage and amperage were set to 40 kV and 40 mA respectively.
  • the energy dispersive detector a nickel filter was used to screen out unwanted wavelengths.
  • Data was collected in the Theta-Theta goniometer at the Cu wavelength from 3.0 to 40.0 degrees 2-Theta using a step size of 0.01 degrees and a step time of 1.0 second.
  • the anti-scatter screen was set to a fixed distance of 1.5 mm. Samples were rotated at 15/min during collection. Samples were prepared by placing them in a silicon low background sample holder and rotated during collection. Data were collected using Bruker DIFFRAC Plus software and analysis was performed by EVA diffract plus software.
  • the PXRD data file was not processed prior to peak searching.
  • peaks selected with a threshold value of 1 were used to make preliminary peak assignments. To ensure validity, adjustments were manually made; the output of automated assignments was visually checked, and peak positions were adjusted to the peak maximum. Peaks with relative intensity of > 3 % were generally chosen. The peaks which were not resolved or were consistent with noise were not selected. A typical error associated with the peak position from PXRD stated in USP up to +/- 0.2° 2-Theta (USP-941).
  • Solid-state NMR (ssNMR) analysis was conducted on a CPMAS probe positioned into a Bruker-BioSpin Avance III 600 MHz ( 1 H frequency) NMR spectrometer. Material was packed into a ZrO2 rotor. A magic angle spinning rate of 15 kHz was used. Spectra were collected at ambient temperature (probe temperature of 25°C.)
  • 13 C ssNMR spectra were collected using a proton decoupled cross-polarization magic angle spinning (CPMAS) experiment.
  • CPMAS proton decoupled cross-polarization magic angle spinning
  • a phase modulated proton decoupling field of 80- 100 kHz was applied during spectral acquisition.
  • the cross-polarization contact time was set to 2 ms and the recycle delay to 3.5 seconds for Form 1 , Form 5, Form 9, Form 10, Form 11 , and 750 mg/g SDD.
  • the number of scans was adjusted to obtain an adequate signal to noise ratio.
  • the 13 C chemical shift scale was referenced using a 13 C CPMAS experiment on an external standard of crystalline adamantane, setting its up-field resonance to 29.5 ppm.
  • 19 F ssNMR spectra were collected using a proton decoupled magic angle spinning (MAS) experiment.
  • a phase modulated proton decoupling field of 80-100 kHz was applied during spectral acquisition.
  • Spectra were collected with a recycle delay of 3.5 seconds for Form 1 , Form 5, Form 9, Form 10, Form 11 , and 750 mg/g SDD. The number of scans was adjusted to obtain an adequate signal to noise ratio.
  • the 19 F chemical shift scale was referenced using a 19 F MAS experiment on an external standard of trifluoroacetic acid (50%/50% v/v in H2O), setting its resonance to -76.54 ppm.
  • a TA Instruments TGA 5500 is used for the thermal analysis portion of the instrument. Samples of approximately 5 mg to 10 mg were weighed into aluminum pans and heated from ambient temperature to 275 °C (for Form 9) or to 200 °C (for Form 11) at 10 °C/minute heating rate under nitrogen purge (10 mL/min for balance and 25 mL/min for sample chamber).
  • a Thermo Nicolet IS20 FT-IR spectrometer equipped with a KBr beamsplitter and a DTGS KBr detector was utilized for TGA-IR analysis.
  • the collection range was 4000 - 400 cm -1 and Happ-Genzel apodization was used for data collection.
  • Background spectra were collected at 8 cm -1 resolution with 64 co-added scans.
  • the IR background is collected with the TGA furnace closed and purged for 2 to 3 minutes.
  • the sample method is set up for a quick spectral collection, as the evolved gases are swept quickly through the gas cell.
  • Each sample spectral data point is a co-added spectrum of five spectra, collected with 8 cm -1 resolution.
  • the total IR collection time is adjusted based on the run length of the TGA.
  • Modulated Differential scanning calorimetry measurement was performed with Discovery DSC 2500 (TA instruments) equipped with a refrigerated cooling accessory. All the experiments were performed in standard/Tzero aluminum pans. The cell constant was determined using indium and temperature calibration was performed using indium and tin as standards. All the measurements were done under continuous dry nitrogen purge (50 mL/min). Approximately 1-5 mg of solid sample was weighed into a Tzero aluminum pan, sealed non-hermetically and heated with heat-cool-heat program.
  • the heat-cool- heat program was heated from -50 to 120°C using a modulate temperature amplitude of ⁇ 1.0°C, a modulation period of 100s, and a ramp rate of 2°C/min, then ramp to -50 °C with a ramp rate of 10°C/min, followed second heating from -50 to 200°C using a modulate temperature amplitude of ⁇ 1.0°C, a modulation period of 100s, and a ramp rate of 2°C/min.
  • the experimental data were analyzed using commercially available software (TA Universal Analysis 2000/Trios software, TA Instruments).
  • Step 1 Preparation of methyl ((S)-1-((2S,4R)-2-(((S)-1-amino-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-4-(trifluoromethyl) pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2-yl)carbamate, compound II (as an organic solution)
  • the compound of formula IV, (2S,4R)-1-((S)-2-((methoxycarbonyl)amino)-3,3- dimethylbutanoyl)-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid (25.4 g, 69.7 mmol, 1.0 equivalent) and methyl ethyl ketone (200 mL, 8 L/kg of compound IV) were combined and stirred at 25 °C.
  • reaction was quenched by the addition of aqueous NaCI (100 mL of a 14 wt% brine solution, 4.0 L/kg of compound IV), stirred 15-30 minutes and phases were separated.
  • the organic phase was washed with a second portion of aqueous NaCI (100 mL of a 14 wt% brine solution).
  • Both aqueous phases were combined and extracted with methyl ethyl ketone (125 mL, 5 L/kg of compound IV) twice. All organic phases were combined and then concentrated by vacuum distillation at 0.3 bar (internal temperature of reaction mixture approximately 30°C) to a concentration of approximately 5L/kg of product.
  • Isopropyl acetate 200 mL, 8 L/kg of compound IV was then added to the mixture and distillation continued to reach approximately 5L/kg of product compound II reaction volume. A second addition of isopropyl acetate (200 mL, 8 L/kg of compound IV) was added, and the distillation process was repeated following the same protocol, ending the distillation at a concentration of 5 L/kg of product compound II. Isopropyl acetate (125 mL, 5 L/kg of compound IV) was added and stirred at 25 °C. A sample was analyzed for water content (Karl- Fischer) with a target of not more than 0.2 wt% water.
  • Step 2 The isopropyl acetate solution of methyl ((S)-1-((2S,4R)-2-(((S)-1-amino-1-oxo- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-4-(trifluoromethyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2-yl)carbamate, compound II, prepared above (assumed quantitative conversion, 69.7 mmol, 1.0 equivalent) was combined with N- methylmorpholine (36.7 g, 40 mL, 0.36 mol, 5.2 equivalents) and stirred at 10 °C.
  • Trifluoroacetic anhydride (38.1 g, 25.5 mL, 0.18 mol, 2.6 equivalents) was charged over 30-60 minutes dropwise, maintaining the reaction temperature at not more than 15 °C. The resulting mixture was stirred for 1 hour at 10 °C. A sample was analyzed for reaction completion (not more than 0.5% compound II present). [NOTE: If the reaction was not complete, maintain stirring for another 60 minutes, and charge additional N- methylmorpholine and trifluoroacetic anhydride (maintaining a 2:1 ratio) if needed]. The reaction was quenched by addition of aq.
  • ammonium hydroxide (28 wt%) (10.7 mL, 76 mmol, 1.1 equivalents) in water (74.1 mL water, 3.0 L/kg of compound IV from previous step). Mixture was stirred for 15-30 min, then stopped and the layers allowed to settle. The aqueous phase was removed, and the organic phase was sampled for internal process control (target of not more than 0.1% methyl ((S)-1-((2S,4R)-2-(((S)-1-cyano-2- ((S)-2-oxopyrrolidin-3-yl)ethyl)carbamoyl)-4-(trifluoromethyl)pyrrolidin-1-yl)-3,3-dimethyl-
  • Step 3 Compound I, CPME solvate (30.09 g, 51.03 mmol, 100 mass%) and Heptane (300 mL, 2047.9 mmol, 100 mass%) was added into a 1000 mL two-piece OptiMax reactor with overhead stirring at 350 rpm and baffle. The mixture was stirred at 20 °C and heated to 70 °C. The mixture was stirred at 70 °C for 12 hours then the mixture was cooled to 25 °C in 5 hours and stirred overnight. The resulting slurry was filtered and washed with Heptane (60 mL, 409.58 mmol, 100 mass%).
  • PXRD was determined for N-(Methoxycarbonyl)-3-methyl-L-valyl-(4R)-N- ⁇ (1S)-1-cyano- 2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide, Form 1 and the PXRD pattern is provided in Figures 1 and 2.
  • Crystals were grown from a solution of N-(Methoxycarbonyl)-3-methyl-L-valyl- (4R)-N- ⁇ (1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L- prolinamide, Form 1 dissolved in 1 -Chlorobutane by slow evaporation of the solution at room temperature.
  • PXRD was determined for N-(Methoxycarbonyl)-3-methyl-L-valyl-(4R)-N- ⁇ (1S)-1-cyano- 2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide, Form 5 anhydrous free form.
  • TGA-IR Thermogravimetric Infra-red Analysis
  • 19 F solid-state NMR peak is ⁇ 0.2 ppm.
  • Form 1 565.0 mg of N-(Methoxycarbonyl)-3-methyl-L-valyl-(4R)-N- ⁇ (1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide, Form 1 was weighed into a 2- dram vial equipped with stirring bar and 2.5 mL of isopropyl acetate was pipetted into the vial. The mixture was stirred at approximately 25 °C in a heat block for approximately 2 days. The mixture was vacuum filtered, and the solids were allowed to sit in ambient air for 3 days.
  • TGA-IR Thermogravimetric Infra-red Analysis
  • Form 12 shows that the structure contains residual void space of 1666 A 3 , which account for 26.9% of the unit cell volume.
  • a solvent mask was calculated, and 420 electrons were found in a volume of 1772 A A 3 in 1 void per unit cell. This is consistent with the presence of 1[C5H10O2] per Asymmetric Unit which account for 448 electrons per unit cell.
  • Table 8-1 Crystal structure data of crystalline N-(Methoxycarbonyl)-3-methyl-L-valyl- (4R)-N- ⁇ (1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L- prolinamide, isopropyl acetate solvate, Form 12.
  • the resulting solution which has a weight percent of API I polymer I acetone 7.5/2.5/90 was atomized into a co-current stream of heated nitrogen, during which the solvent was removed to form SDD particles.
  • the SDD particles were subjected to a secondary drying step in a vacuum tray dryer to remove residual acetone solvent from the SDD to an acceptable level (acceptable level is ⁇ 5000 ppm (acetone) by guidance, Test per USBD-334 which is usually below 0.05%).
  • N-(Methoxycarbonyl)-3-methyl-L-valyl-(4R)-N- ⁇ (1S)-1-cyano-2-[(3S)-2-oxo pyrrolidin-3-yl]ethyl ⁇ -4-(trifluoromethyl)-L-prolinamide/HPMCAS-MG SDD was characterized by PXRD (Fig. 6), 13 C and 19 F solid state NMR (Figs. 25-26) and modulated differential scanning calorimetry (mDSC) (Fig. 34).
  • Powder X-ray diffraction analysis was conducted using a Bruker AXS D8 Endeavor diffractometer equipped with a Cu radiation source (K-a average).
  • the divergence slit was set at 15 mm continuous illumination.
  • Diffracted radiation was detected by a PSD- Lynx Eye detector, with the detector PSD opening set at 4.10 degrees.
  • the X-ray tube voltage and amperage were set to 40 kV and 40 mA respectively.
  • Data was collected in the Theta-Theta goniometer at the Cu wavelength from 3.0 to 40.0 degrees 2-Theta using a step size of 0.01 degrees and a step time of 1.0 second.
  • the antiscatter screen was set to a fixed distance of 3.0 mm. Samples were rotated at 15/min during collection. Samples were prepared by placing them in a silicon low background sample holder and rotated during collection. Data were collected using Bruker DIFFRAC Plus software and analysis was performed by EVA diffract plus software.
  • the PXRD data file was not processed prior to peak searching.
  • peaks selected with a threshold value of 1 were used to make preliminary peak assignments. To ensure validity, adjustments were manually made; the output of automated assignments was visually checked and peak positions were adjusted to the peak maximum. Peaks with relative intensity of > 3 % were generally chosen. The peaks which were not resolved or were consistent with noise were not selected. A typical error associated with the peak position from PXRD stated in USP up to +/- 0.2° 2-Theta (USP-941).
  • a sample of Form 22 single crystal was examined by SXRD.
  • SXRD was performed on a Bruker D8 Venture diffractometer at 298K. Data collection consisted of omega and phi scans.
  • the structure was solved by intrinsic phasing using SHELX software suite in the monoclinic space group P2i.
  • the structure was subsequently refined by the full-matrix least squares method. All non-hydrogen atoms were found and refined using anisotropic displacement parameters. The final R-index was 4.8 %.
  • Table 2 contains structural data from the SXRD analysis of Form 22.
  • the ORTEP diagram for the asymmetric unit for Form 22 is presented in Figure 3, with displacement parameters at 50% probability.
  • 13 C ssNMR spectra were collected using a proton decoupled cross-polarization magic angle spinning (CPMAS) experiment.
  • CPMAS proton decoupled cross-polarization magic angle spinning
  • a phase modulated proton decoupling field of 80- 100 kHz was applied during spectral acquisition.
  • the cross-polarization contact time was set to 2 ms and the recycle delay to 3.5 seconds.
  • the number of scans was adjusted to obtain an adequate signal to noise ratio.
  • the 13 C chemical shift scale was referenced using a 13 C CPMAS experiment on an external standard of crystalline adamantane, setting its up-field resonance to 29.5 ppm.
  • 19 F ssNMR spectra were collected using a proton decoupled magic angle spinning (MAS) experiment.
  • a phase modulated proton decoupling field of 80-100 kHz was applied during spectral acquisition.
  • Spectra were collected with a recycle delay of 3.5 seconds. The number of scans was adjusted to obtain an adequate signal to noise ratio.
  • the 19 F chemical shift scale was referenced using a 19 F MAS experiment on an external standard of trifluoroacetic acid (50%/50% v/v in H2O), setting its resonance to -76.54 ppm.
  • Automatic peak picking was performed using Bruker-BioSpin TopSpin version 4.1 software. Generally, a threshold value of 5% relative intensity was used for preliminary peak selection.
  • Table 11-2 contains structural data from the SXRD analysis of Form 22.
  • the ORTEP diagram for the asymmetric unit for Form 22 is presented in Figure 39, with displacement parameters at 50% probability.
  • Table 11-2 Crystal structure data of crystalline Form 22 of N-(Methoxycarbonyl)-3- methyl-L-valyl-(4R)-N- ⁇ (1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ⁇ -4- (trifluoromethyl)-L-prolinamide.

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Abstract

La présente divulgation concerne des formes solides de N-(méthoxycarbonyl)-3-méthyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]éthyl}-4-(trifluorométhyl)-L-prolinamide, I, telles que des formes anhydres, une forme amorphe, un solvate de cyclopentyle éther méthylique, un solvate d'acétate d'isopropyle, et un solvate d'acétate d'éthyle de celui-ci de formule (I) ainsi que des compositions pharmaceutiques comprenant les formes solides et des méthodes de traitement utilisant les formes solides.
PCT/IB2024/055548 2023-06-09 2024-06-06 Formes solides de n-(méthoxycarbonyl)-3-méthyl-l-valyl-(4r)-n- {(1s)-1-cyano-2-[(3s)-2-oxopyrrolidin-3-yl]éthyl}-4-(trifluorométhyl)-l-prolinamide et leurs solvates Pending WO2024252327A1 (fr)

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US3773919A (en) 1969-10-23 1973-11-20 Du Pont Polylactide-drug mixtures
US4485045A (en) 1981-07-06 1984-11-27 Research Corporation Synthetic phosphatidyl cholines useful in forming liposomes
US4544545A (en) 1983-06-20 1985-10-01 Trustees University Of Massachusetts Liposomes containing modified cholesterol for organ targeting
US5013556A (en) 1989-10-20 1991-05-07 Liposome Technology, Inc. Liposomes with enhanced circulation time
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WO2021250648A1 (fr) * 2020-09-03 2021-12-16 Pfizer Inc. Composés antiviraux contenant du nitrile
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